A. We reviewed the serum sodium values of 263 lung cancer patients before the initiation of treatment. In contrast to none of the 130 non-small cell lung cancer (NSCLC) patients, 21 of 133 (16%) small cell lung cancer patients had hyponatremia (p=0.0001). Eleven of 21 patients with hyponatremia had tumor cell lines available and 9 expressed ANF mRNA, 7 expressed AVP mRNA, and 5 of 11 cell lines produced both ANF and AVP mRNA. All of the 11 cell lines produced ANF mRNA, AVP mRNA, or both. From these studies we have observed that all tumor cell lines studied from SCLC patients with hyponatremia produce ANF mRNA or AVP mRNA, or both. Atrial natriuretic peptide may be the previously hypothesized third factor and play an important role in the pathogenesis of hyponatremia in some patients with SIADH. B. The atrial natriuretic factor A receptor mRNA has been detected on small cell lung cancer cells by PCR analysis of cDNA from the cell lines and RNase protection assay. Binding studies with iodinated ANF showed saturable binding but the number of sites were to low to accurately estimate. The cells respond to exogenously added atrial natriuretic factor with an increase in intracellular cGMP, similar to the normal receptors. Therefore, there appear to be functional ANF receptors on the surface of small cell lung cancer cells. C. The serum and urine calcitonin values of 86 different individuals were studied by radioimmunoassay which included 20 nonsmokers, 17 smokers, and 49 patients with small cell lung cancer. The urine values were the most different in these three groups of individuals (p is less than 0.00001). RNase protection assays (RPA) and RIAs of 11 tumor cell lines from these patients with small cell lung cancer showed some had elevated serum and urine calcitonin values but did not have ectopic calcitonin production in their tumor cell lines. Therefore it appears that elevated calcitonin levels in patients with lung cancer can come from a source other than the tumor cells.